Cisplatin, cis-[PtCl2(NH3)2] is one of the three most widely used clinical agents in the treatment of a variety of solid tumors(1). It is believed to kill tumor cells by binding irreversibly to the DNA, mainly to two adjacent guanines on the same strand, inducing a kink in the DNA that is recognized by cellular proteins that bind the cisplatin-modified DNA(2). It is the Pt-DNA adducts that are responsible for the induction of apoptosis and eventual cell death(3). Despite its efficacy in the treatment of various neoplastic diseases, including testicular and ovarian tumors, it's clinical utility is restricted by its low solubility, toxicity and especially tumor resistance(4). Second generation drugs such as carboplatin (Pt(CBDCA)(NH3)2, CBDCA=1,1-cyclobutanedicarboxylate) exhibit reduced nephrotoxicity but fail to overcome the tumor resistance probably due to the fact that they form the same spectrum of DNA adducts as does cisplatin(5).
Overcoming the resistance is one of the major goals in the development of novel platinum drugs and hence new compounds that deviate from the classic structure-activity relationship (SAR) have been designed, synthesized and screened(6). The SAR, first formulated by Cleare and Hoeschele, influenced medicinal chemists to direct their efforts to the preparation of neutral platinum(II) complexes with two inert ligands in the cis configuration and two semi-labile leaving groups(7).
It was generally accepted that a cis configuration of the two leaving groups is essential for anti-tumor activity of cis-diaminedichloroplatinum (cis-DDP). This was the situation for more than two decades until Farrell et. al have reported that replacing one or both NH3 ligands in trans-PtCl2(Am1)(Am2), wherein Am1, Am2═NH3, or planar amine ligands such as quinoline, thiazole, pyridine or benzothiazole, (e.g. trans-[PtCl2(NH3)(pyridine)], trans-[PtCl2(NH3)(thiazole)], trans-[PtCl2(NH3)(quinoline)], and trans-[PtCl2(NH3)(benzothiazole)]) substantially enhances the cytotoxicity of the trans geometry(8). Nguyen, H. D. et al. Vietnam J. of Chem. (2001) 39(4), 111–114 describe the synthesis of cis-PtCl2 complexes containing quinoline and primary and secondary amines and discuss their 1H-NMR spectra. Tran, T. D. et al. Tap Chi Duoc Hoc (2001) 6, 6–8 describe cis-PtCl2 complexes containing two amine-containing ligands, one being an aromatic pyridine or benzylamines and the other a aliphatic cyclic amine (morpholine or piperidine) and discuss the complexes IR and Raman spectra. Tran T. D. et al. Vietnam J. of Chem. (2001) 39(3), 99–102 describe the synthesis of cis-PtCl2 complexes containing piperidine and aromatic amine or an amine substituted with an aromatic amine, their IR, Raman and UV spectra. Furthermore, the complexes were tested for cell cytotoxicity on human liver cancer cells. Tran, T. D. et al. Tap Chi Duoc Hoc (Vietnam J. of Chem.) (1997) 35(2), 21–23 describe the synthesis of cis-PtCl2 complexes containing guinoline and an amine selected from morpholine, cyclohexylamine, piperidine or benzylamine, their UV and IR spectra and their biological activity for reducing the germination of kernels. Jonson Matthey Pub. Ltd. Co. EP-A-0727430 (1996) describes cis-Pt complexes of formula Pt(X)(Z)(A)2 and their activity against cancer cells. A is a leaving group (e.g. halogen, hydroxy, carboxylate, or together form a bi-dentate carboxylate, or sulphate) and X is NH3 or mono- or dialkyl substituted NH3. Z is a substituted amine, preferably a 5- or 6-membered monocyclic or an 8–10 membered polycylic amine, especially substituted pyridine or bycylic amine where the amine is coordinated through the nitrogen atom. Ivanova, N. A. et al. Russian J. Coord. Chem. (1993) 19(12) 856–863 describe the synthesis of PtX2 complexes with piperazine, where X may be Cl or Br. The synthesized complexes were analyzed with vibrational spectroscopy for elucidating the piperazine conformation. Cattalini, L. et al. J. Chem. Soc. Dalton Transactions (1993) 233–236 describe cis and trans PtCl2 complexes containing two amine ligands, the amine chosen from pyridine, substituted pyridine, morpholine, piperidine and dimethylamine. Shionogi & Co. EP-A-0273315 (1988) disclose cis-PtX2(NH3)(Am) complexes. X maybe Cl, I, nitro or a cyclic moiety and Am is a substituted C2-7N and their antitumor activity. Wong et al. Chem. Rev. (1999) 99(9), 2451–2466 review platinum-based antitumor drugs mentioning cis-Pt complexes.
In addition, Navarro-Ranniger and co-workers demonstrated that trans-PtCl2[NH2CH(CH3)2][NH(CH3)2] has interesting pharmacological properties(9) and Natile et. al. reported that trans-PtCl2(iminoether)2 is also active against several human cancer lines(10). Another example of a non-classical complex that is in phase 2 of clinical trials is the trinuclear Pt complex BBR3464 that is a quadruply charged cation(11).
The importance of the non-classical platinum compounds stems from the fact that they were designed to form a spectrum of DNA adducts that is distinct from that formed by cisplatin and carboplatin and hence they can circumvent acquired Pt resistance(12).
Generally, trans-diaminedichloroplatinum(II) analogues have lower solubility in aqueous solution than their cis counterparts, resulting in limited bioavailability. One way of increasing the aqueous solubility is by adding a charge to the complex. Farrell et al. have put some effort in overcoming the poor water solubility of compounds of the type trans-[PtCl2(NH3)(Am1)](Am1=planar ligand), while retaining the trans orientation of the NH3 and the planar ligand and electroneutralilty of the square-planar entity. The trans-platinum complex trans-[PtCl(PyAc—N,O)(NH3)] (PyAc=pyridin-2-yl acetate, N-donors are trans) and its cis isomer were synthesized and the trans isomer have shown improved solubility (ca. 4–5 mmol L−1) in water, compared to analogous complexes trans-[PtCl2(NH3)(Am1)](Am1=planar ligand)(13). On the other hand, the cationic charges of the platinum complexes prepared by Farrell et al. and also by Hollis et al. reside on the metal center and result from the substitution of one or the anionic chloride ligands by a neutral ligand(14).